1. Field of Invention
This invention relates to novel inhibitors of nitric oxide synthase (NOS) that act at the level of enzymatic activity inhibition. In particular, this invention relates to the treatment of acute and chronic inflammatory conditions by the administration of NOS inhibitors.
2. Background
Nitric oxide (NO) is a gas radical produced by the enzyme nitric oxide synthase (NOS). There are three NOS enzymes, or isoforms, in mammals. A low level of NO is continuously produced by isoforms I and III, the constitutive or cNOS that are activated by calcium and the calcium-binding protein calmodulin. The NO produced is functional in vascular and nervous systems, and is important in the regulation of blood pressure and in neurotransmission. A high level of NO is produced by isoform II, the inducible or iNOS that is regulated by gene expression. The high level of NO is functional in the immune system as a means of host defense.
In the immune system, NO produced by one particular type of leukocytes, namely the macrophages, contributes to leukocyte killing of bacteria, fungi and tumor cells. Although meant to be protective, excess NO and NO metabolites, or reactive nitrogen intermediates, may also contribute to the destructive aspects of an immune response, particularly in chronic inflammation, by non-specific destruction of cellular metabolic machinery within a circumscribed area of NO release. Such non-specific destruction, if excessive, can lead to any one of a number of inflammatory diseases or syndromes, inclusing autoimmune diseases, such is rheumatoid arthritis.
Interfering with the production of NO provides a means of modulating inflammatory reactions and of inhibiting destructive sequelae of a chronic inflammatory immune response. However, given that NO is highly reactive by nature, inhibitors which inhibit the NO radical directly would not be expected to be as effective as an inhibitor which blocks the synthesis of the NO radical.
A variety of inhibitors of the nitric oxide synthases has been reported, as seen from the following examples. U.S. Pat. No. 5,585,402 to Moncada and Palmer (1996) discloses N-monomethyl-L-arginine. U.S. Pat. No. 5,674,907 to Southan, Salzman and Szabo (1997) discloses mercapto derivatives as NOS inhibitors. U.S. Pat. No. 5,449,688 to Wahl, Allen and McCartney-Francis (1995) discloses a method of treating chronic inflammatory diseases using compounds including nitric oxide synthase inhibitors. However, these compounds are mostly generated by chemical synthesis, and may have additional adverse effects besides inhibiting the NOS enzymes. Hence, inhibitors from natural sources are being sought after. It is anticipated that additional compounds may prove to have fewer side effects and greater selectivity in inhibiting the inducible nitric oxide synthase enzyme.
Epigallocatechin-3-gallate (EGCG) is the major polyphenol from green tea. Since tea is one of the most widely consumed beverages, second only to water, tea-derived EGCG may be much safer. Several beneficial effects of EGCG are known, as seen from the following examples. U.S. Pat. Nos. 5,318,986 and 5,670,154 both granted to Hara and Honda (1994, 1997) disclose that tea polyphenols including EGCG inhibit the enzyme activity of alpha amylase and tyrosinase. U.S. Pat. No. 5,605,929 to Liao and Liang (1997) discloses catechins including EGCG inhibit the enzyme activity of 5 alpha reductase. U.S. Pat. No. 5,391,568 to Chung (1995) discloses that EGCG inhibits lung cancer in a mammal. However, the effect of EGCG on the level of enzyme activity of nitric oxide synthase is unknown.
It is the object of the present invention to provide a method for the treatment of chronic and acute inflammatory conditions. More specifically, it is an object of the present invention to provide a method for the treatment of conditions wherein an agent that inhibits nitric oxide synthase is administered.
These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.